Technical field of invention
The present invention relates to a novel process for preparation of an intermediate which is useful in synthesis of compounds which have commercial importance in the field of Pharmaceuticals, pesticides, dyes etc.
Background of the invention
Several synthetic routes have been disclosed in prior art for synthesis of 6-fluoro-3,4-dihydro-2(H)-benzopyran-2-carboxaldehyde (2), some of which, relevant to the subject matter of the present invention, are discussed below:
US 4,654,432 teaches a process for synthesis of aldehyde (2) from 6-fiuoro-4-oxo-dihydro-4H-l-benzopyran-2-carboxylic acid (3), as depicted in synthetic scheme 1. The acid (3) is hydrogenated using 10% Pd/C catalyst at normal pressure and room temperature to obtain 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxylic acid (4). The acid (4) is esterified with ethanolic HC1 to corresponding ethyl ester (5) which is reduced with sodium dihydro-bis(2-methoxyethoxy)aluminate in a mixture of toluene and benzene to obtain 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-methanol (1) which in turn is oxidized by treatment with oxalyl chloride in a mixture of dichloromethane and dimethyl sulfoxide (DMSO) at -60°C to aldehyde (2).


The publication, Yihui Bai et. al; Journal of Chemical Research, 2006, 12, 807-808 discloses a process wherein the acid (3) is hydrogenated in presence of 10% Palladium on carbon at pressure 2Mpa at 70-80°C to obtain (4) which is further reacted with ethyl chloroformate to give mixed anhydride intermediate insitu which is reduced to obtain alcohol (1). Alcohol (1) is oxidized with pyridinium chlorochromate (PCC) in presence of SiO2 in dichloromethane to afford desired aldehyde (2). (Synthetic scheme 2)

The methods reported in prior art described above suffer from following disadvantages: i) Requires very low temperatures, which makes the process inconvenient to
carry out on an industrial scale, ii) Use of expensive solvents like DMSO and reagents like sodium dihydro-
bis(2-methoxyethoxy)aluminate renders the process less economical, iii) Reagents which contain heavy metals like palladium and chromium are used
which render the process less environment friendly, iv) Hazardous reagents like ethyl chloroformate and PCC are used which cause
handling problems on large scale.

A general synthetic method for oxidation of primary alcohols to aldehydes using NaOCl in presence of tetra methyl pyridinium oxide (TEMPO) and catalytic amount of KBr is described in Organic syntheses, Coll. Vol. 8, p.367 (1993); Vol. 69, p.212 (1990).
The process of present invention is simpler and it overcome the drawbacks of earlier methods
Summary of the invention
The present invention provides a novel process for preparation of 6-fluoro-3,4-dihydro-2(H)-benzopyran-2-carboxaldehyde (2} comprising the steps of:
1. esterification of 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxylic acid (4) to
obtain ester (7),
2. reduction of ester (7) to afford 6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol
OX and
3. oxidation of alcohol (1) with alkali metal hypochlorite in presence of tetra methyl
pyridinium oxide (TEMPO) and alkali metal halide to obtain 6-fluoro-3,4-
dihydro-2(H)-benzopyran-2-carboxaldehyde(2).
Description of the invention
The present invention provides a novel process for preparation of 6-fluoro-3,4-dihydro-2(H)-benzopyran-2-carboxaldehyde (2) comprising the steps of:
1. esterification of 6-fiuoro-3,4-dihydro-2H-l-benzopyran-2-carboxylic acid (4) to
obtain ester (7),
2. reduction of ester (7) to afford 6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol
(1),and
3. oxidation of alcohol (1) with alkali metal hypochlorite in presence of tetra methyl
pyridinium oxide (TEMPO) and alkali metal halide to obtain 6-fluoro-3,4-
dihydro-2(H)-benzopyran-2-carboxaldehyde (2).

The steps involved in the synthesis of aldehyde intermediate (2) according to the process of present invention are depicted in synthetic scheme 3 below:

In a preferred embodiment, the present invention provides a novel method for oxidation of the alcohol (1) using sodium hypochlorite as an oxidizing agent in presence of TEMPO, which is employed as a radical initiator and catalytic amount of alkali metal halide.
The esterification of the acid (4) is carried out with lower alcohol in presence of a strong acid. The lower alcohol is selected from a group consisting of methanol, ethanol, propanol, isopropanol and the acid is selected from HC1, H2SO4, p-toluenesulphonic acid and the like. Preferably methyl ester (7, R=CH3) is prepared by reacting acid (4) with methanol in presence of H2SO4 under reflux conditions. The ester (7) can also be obtained by various methods known in the art.
The reduction of ester (7) can be achieved by treatment with reducing agents such as lithium aluminium hydride, BH3-THF, alkali metal borohydrides, of which alkali metal borohydrides are preferred.

The reduction of methyl ester (7, R=CH3) is carried out by using alkali metal borohydrides such as sodium borohydride, potassium borohydride and the like. Solvent employed for reduction is usually an inert solvent selected from group of alcohols such as methanol, ethanol, propanol, isopropanol; ethers such as tetrahydrofuran(THF), dioxane; water and mixtures thereof. More preferably a mixture of water and THF is employed. The solvent mixture of THF and water is in the ratio of 1: 10 to 10:l(v/v), more preferably in a ratio of 2:1 to 6:1, most preferably in the ratio of 4:l(v/v).
The oxidation of alcohol (1) is carried out by using oxidizing agent such as hypochlorites of alkali earth metals and alkaline earth metals that include, but are not limited to, sodium hypochlorite, calcium hypochlorite and the like. Most preferred oxidizing agent is sodium hypochlorite.
Molar ratio of hypochlorite with respect to alcohol(1) is in the range of 0.5 to 3.0 molar equivalents, most preferably 1.01 molar equivalent of hypochlorite is employed.
The oxidation reaction is carried out in presence of radical initiator such as tetra methyl pyridinium oxide (TEMPO) and catalyst selected from the group of alkali metal halides such as KBr, NaBr, KJ, NaI and the like. Reaction is carried out at a temperature ranging from -10 to 50°C, most preferably at a temperature of 0-5°C.
Molar ratio of alkali metal halide with respect to alcohol ( 1 ) is in the range of 0.05 to 1 molar equivalents, most preferably 0.15 molar equivalents of alkali metal halide is employed.
The oxidation is carried out in a biphasic reaction medium comprising of an organic solvent and 10% aqueous sodium bicarbonate solution. The organic solvent employed in oxidation step is selected from the group of, but is not limited to, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; aliphatic esters such as methyl acetate, ethyl acetate, propyl acetate; ethers such as diethyl ether,

di-isopropyl ether and mixtures thereof. More preferably halogenated hydrocarbons are used as a solvent, most preferably dichloromethane.
The process of present invention has following advantages over the prior art methods:
1. Avoids use of heavy metal containing reagents like PCC and heavy metals like Pd
thereby rendering the process more environment friendly.
2. Avoids use of expensive solvents like DMSO.
3. Eliminates the need to employ very low temperatures.
4. Avoids use of hazardous reagents like ethyl chloroformate and PCC.
The aldehyde intermediate (2) can be further converted to nebivolol hydrochloride through processes known in art, for instance the process disclosed in US 4,654,432.
The invention is illustrated by following examples which should not be construed as limiting the scope of the invention:
Example 1:
Acid (4) (10 g) was dissolved in 50 ml of methanol, sulphuric acid (0.05 ml) was added and the reaction mixture was heated to reflux. After completion of the reaction, methanol was distilled off, water was added to the residue and the resulting mixture was extracted with dichloromethane. The organic layer was separated and concentrated to get crude methyl ester (7), which was crystallized from cyclohexane. Yield: 9.1 g (85%)
Example 2:
Sodium borohydride (5.4 g) was charged to 200 ml mixture of THF and water (4:lv/v). A solution of methyl ester (7) (10 g) in THF (20 ml) was charged slowly under stirring. Reaction mixture was stirred till completion of the reaction and then reaction mass was acidified using 1:1 HC1. The solvent was distilled off under reduced pressure. Water was added to the residual mass and extracted with dichloromethane. The organic layer was

separated and concentrated. The alcohol (1) thus obtained was further purified by crystallization from cyclohexane. Yield: 7.2 g (80 %).
Example 3:
Alcohol (1} (10 g) was dissolved in 100 ml of dichloromethane. A solution of potassium bromide (1 g) in 25 ml water and TEMPO (100 mg) was charged to it. Reaction mixture was cooled to 0-5 °C and 10% aqueous solution of sodium bicarbonate was charged to the above reaction mass. 8% sodium hypochlorite solution (52 ml) was slowly added to the reaction mixture maintaining the temperature below 5°C. After the completion of reaction, organic layer was separated, washed with water and concentrated to obtain aldehyde (2) as an oily mass. Yield: 8 g (80 %)

The present invention provides a novel process for preparation of 6-fluoro-3,4-dihydro-2(H)-benzopyran-2-carboxaldehyde (2) comprising the steps of:
1. esterification of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (4) to obtain ester (7),
2. reduction of ester (7) to afford 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol (1), and
3. oxidation of alcohol (1) with alkali metal hypochlorite in presence of tetra methyl
pyridinium oxide (TEMPO) and alkali metal halide to obtain 6-fluoro-3,4-dihydro-2(H)-benzopyran-2-carboxaldehyde(2).